DE2014346A1 - New unsaturated amines and processes for their preparation - Google Patents

Description

CIBA AKTIENGESELLSCHAFT, BASEL (SWITZERLAND).

Case 6715 / I-3
Germany

New unsaturated amines and processes for their preparation.

The invention relates to l- (sec.amino) -2-hydroxy-3- [p- (R-alk-0) phenoxy] propanes the formula

OH
R ^ Ik-O-Ph-O-CH ₂ -CH-CH ₂ -NH-R ₁ , (X)

wherein alk is an alkylene radical and R is an unsaturated aliphatic hydrocarbon radical, R- is an ali-

00 9 84 1/197 8

"■ 2014348

phatic hydrocarbon radical with up to 15 carbon atoms, which can also be interrupted by heteroatoms such as oxygen, sulfur or nitrogen and / or can be substituted by hydroxyl groups, a cycloaliphatic hydrocarbon radical with up to 15 carbon atoms or an araliphatic hydrocarbon radical with up to 15 carbon atoms, which can be substituted W in particular in the aromatic nucleus, for example as detailed below, and in which Ph is an optionally substituted 1,4-phenylene radical, and their condensation products with aldehydes or ketones, as well as processes for the preparation of these compounds.

The alkylene radical alk is in particular a lower alkylene radical with 1-3 carbon atoms, especially methylene.

The radical R is above all a propenyl or straight or branched propenyl group connected in any position ^ Butenyl, pentenyl or hexenyl radical or a corresponding one Remainder with triple bond; R is primarily the vinyl radical.

The radical R-alk- is preferably the allyl, methallyl or propargyl radical. . .

The aliphatic hydrocarbon radicals R are above all lower saturated or unsaturated aliphatic ones Hydrocarbon radicals in question, especially lower alkyl radicals. Lower straight or special are preferred branched alkyl radicals with up to 5 carbon atoms, such as Methyl, ethyl, especially abor ^ aobutyl, 2-methylbutyl, 3-

201Λ346

Methyl-butyl and very particularly secondary or tertiary alkyl radicals of this type, such as sec-butyl, pentyl- (2), pentyl- (3), 1,1-dimethyl-propyl, tert-butyl and especially isopropyl. Lower unsaturated aliphatic hydrocarbon radicals are above all those of the above formula Mention R-alk-. .

Interrupted by heteroatoms or by hydroxyl groups substituted aliphatic hydrocarbon radicals

are mainly lower oxa-alkyl radicals, especially those that derive from the preferred alkyl radicals mentioned, e.g. alkoxy-ethyl or -propyl radicals, or hydroxyalkyl radicals, such as

• ■ - -

ß-hydroxyethyl or ß- or 7-hydroxypropyl radicals.

The main cycloaliphatic radicals are saturated or unsaturated cycloalkyl or cycloalkyl-lower alkyl radicals to be mentioned, such as above all Cyclbpropyl-, Cyclobutyl-, Cyclopentyl, cyclohexyl or cycloheptyl radicals, as well as methyl, ethyl or propyl radicals carrying these radicals, as well as sol-. j before radicals which have a double bond at a suitable point on the ring or an alkylene chain, as well as lower alkyl, e.g. methyl or ethyl substitution products of these Groups, or groups whose rings contain an endo bond or an endoalkylene group.

Araliphatic carbon residues are in particular Aryl-lower alkyl, such as especially phenyl-lower alkyl, wherein the lower alkyl group has 1-3 carbon atoms

BATH ORIGINAL

9841/1978

2014341

has, in particular benzyl, 1- or 2-phenylethyl or . 2- or 3-phenyl-propyl or 3-phenyl-propyl (2) radicals. In of these araliphatic hydrocarbon radicals, the aryl radicals in particular can be substituted one, two or more times be, e.g. by lower alkyl groups such as methyl or ethyl, lower alkoxy groups such as methoxy, ethoxy or methylenedioxy groups, Halogen atoms, such as fluorine, bromine or, in particular, chlorine atoms, and / or trifluoromethyl groups.

"The 1,4-phenylene radical Ph can also be substituted

be, e.g. by lower alkyl groups such as methyl or ethyl, lower alkoxy groups such as methoxy, ethoxy or methylenedioxy groups, Halogen atoms, such as fluorine, bromine or especially chlorine atoms, trifluoromethyl groups, nitro groups, Amino groups, acylamino groups such as lower alkanoylamino groups, e.g. acetylamino groups, groups of the above Formula R-alk-O-, phenyl-, phenoxy-, alkyloxyalkyl-, e.g. the named, phenylalkoxy, cyano, cyano-alkyl, carboxy, Carboxy-alkyl, mercapto, alkylmercapto, alkenyl, alkynyl, alkanoyl, benzoyl, phenylalkanoyl or phenylsulfonyl groups. However, this radical is preferably unsubstituted.

Condensation products of compounds of the formula I with aldehydes or ketones are, in particular, compounds the formula

R-nlk-a-Ph-O-CH, -CH GK _n

0 NR ₁ (Ia),

X BATH

009841 / 1.9 78

•. 2QT434B

wherein R., alk, Ph and R have the meanings given und.X represents an optionally substituted alkylidene group. X is above all a lower alkylidene group, e.g. methylene, ethylidene, propylidene or isopropylidene, or a benzylidene or pyridylraethylidene group. the Benzylidene or pyridylmethylidene radicals can be unsubstituted or carry one, two or more substituents. The main substituents are lower alkyl radicals, lower alkoxy groups, halogen atoms and trifluoromethyl groups, especially those mentioned.

The new compounds have valuable pharmacological properties, so they inhibit, as can be shown in the dose range of 0.01-30 mg / kg iv on the cat anesthetized with Dial after isoproterenol administration, the cardiac ß- receptors, preferably before the vascular and bronchialeri β-receptors, and also show a β-blocking effect in a concentration of 1 χ 10 to 1 χ 10 g / ml on the isolated rabbit heart after isoproterenol administration. They also inhibit the circulatory reflexes (CSR), as shown in a dose of 0.03-30 mg / kg iv on the cat's blood pressure. The new compounds can therefore be used medicinally as β-blockers and antihypertensors for cardiovascular diseases or psychosomatic symptoms of this kind.

The compounds of the formula are particularly valuable

009841/1978

OH

R-alk-O- <f ^x > -0-CH ₂ -CH-CH ₂ -NH-R

where R and alk have the meaning given above and R, an aliphatic hydrocarbon radical, especially a lower alkyl radical with up to 5 carbon atoms, especially a branched lower alkyl radical of this type, and primarily a secondary or tertiary alkyl radical with at most 5 carbon atoms, and especially the tert-butyl or better represents the isopropyl radical, and their condensation products with lower alkanals or alkanones.

From this group stand out with regard to their effects those compounds in which the radical R-alk is the allyl, methallyl or propargyl radical.

¹ A compound which is particularly preferred in view of its effect is l-isopropylamino-2-hydroxy-3- (pallyloxyphenoxy) propane of the formula

CH = CH-CH _o -2 2

The new compounds are obtained by methods known per se.

It is expedient to use a compound of the formula

X "
R-alk-O ~ Ph-0-0H ₂ -CH ~ CH ₂ -X, (II)

0093A1 / 1978

wherein R, alk and Ph have the meanings given, X "denotes the hydroxyl group and X 'denotes a reactive esterified hydroxyl group or X" and X ¹ together form an epoxy group, with an amine of the formula R ₁ -NHp, in which R .. the has given meaning, or a condensation product thereof with an aldehyde or ketone, for example a compound of the formula

R ₁ - N = X,. (HI)

wherein Rv and X have the meanings given to.

A reactive esterified hydroxyl is, for example, a * as acid with a strong organic or inorganic acid, especially with a hydrohalic acid, Zs-B, the chlorine :, bromine or iodide, or with a sulfonic acid such as a _{Arylsulfölsäure.,:} For example, of p-toluenesulfonic acid, esterified, hydroxyl group ^ The reaction is carried out in a customary manner, if a reactive ester is used, advantageously in the presence of a basic condensing agent or an excess of amine. .

You can also, for example, in a connection the formula

OH

R-alk-O ^ h-0-QH JjHrCH -M

"in which R, alk and Ph have the meanings given, or ' in a" kbndensafcionsprodukt thereof with an aldehyde or ketone, for example in a compound of ^ formula

00 9841/197 8

20U3A6

R-alk-O-Ph-O-CH -GH CH ₀

2 ι ι 2

O NH, (V) X

wherein R, alk, Ph and X have the meanings given, the Introduce remainder R.

The radical R is introduced in the usual way, expediently by reaction with a reactive ψ ester of an alcohol of the formula R, OH.

A reactive ester is, for example, that of a strong organic or inorganic acid, such as especially a hydrohalic acid, e.g. hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid, or a Sulfonic acid, such as an aryl sulfonic acid, e.g., p-toluenesulfonic acid.

The reaction is advantageously carried out in the presence of a basic condensing agent or one ™ uses an excess of amine.

You can also use a phenol of the formula

R - alk - 0 - Ph - OH, (Vl)

wherein R, alk and Ph have the meanings given, with a compound of the formula

X »
X'-OH ₂ -CH-CJH ₂ -MH-R ₁ ', (VII)

where R has the meaning given, X " ^{denotes the hydroxyl group and X 1} denotes a reactive esterified hydroxyl group

009841/1979

■ - - 9 - - ..-. ■ "■," / ■■■. '■■

20H346

or X "and X ¹ together form an epoxy group, or with.> a condensation product of a compound in which X" denotes the hydroxyl group, with an aldehyde or ketone, for example with a compound of the formula

X'-CH ^ -CH- -CH ₀

² II *

I I

0 NR ₁ , (VIII)

wherein X ¹ denotes a reactive esterified hydroxyl group and X and R, have the meanings given, react. S.

A reactive esterified hydroxyl group is in particular one of those mentioned above for X ¹ . The implementation is carried out in the usual way. When using the esters, it is expedient to proceed in the presence of an acid-binding condensing agent, in particular a condensing agent suitable for salt formation with the phenol, or a metal, such as an alkali salt, for example the sodium salt, of phenol is used. So one can work in the presence of alkali alcoholates.

Furthermore, the new compounds can be obtained if one is in a phenol of the formula '.. ■>. "

OH
HO-Ph-O-CH ₂ -CBI-CH ₂ -NH-R ₁ , (IX)

wherein Ph and R have the meanings given above, or in a condensation product thereof with an aldehyde or

AiAI

Ketone, e.g. in a phenol of the formula

HO-Ph-O-CH ₀ -CH

2 y j 2

O Ν — R

wherein Ph, X and R have the meanings given, the phenolic Hydroxyl group substituted in the usual way by the radical R-alk-, in which R and alk have the above given ^ have meaning.

The phenol is expediently used for this purpose, preferably in the presence of condensing agents which form metal salts with phenolic hydroxyl groups, such as carbonates or alcoholates of alkali metals, or a metal salt of phenol, in particular an alkali metal salt, with a reactive esters, especially one of those indicated above, of an alcohol of the formula R-alk-OH.

The new compounds of formula I can also be obtained ^ if one in a 1- (R, -amino) -2-hydroxypropane, that in the 3-position is the remainder of the formula

R - alk - 0 - Ph - 0 -

wherein R, alk, Ph and R have the meanings given, and that on the nitrogen atom and / or on the 2-hydroxy group has a residue that can be split off by hydrolysis, splits it off. Such radicals are, for example, acyl radicals, ina-. special those of carboxylic acids, such as Qxyoarbonylreste, such as the benzyloxycarbonylrest or the tri-

009841/1978

chloroethoxycarbonyl radical, or the tert-butoxycarbonyl radical, or Aeylreste of aliphatic carboxylic acids en j, such as lower Alkanoyl radicals |, e.g. the acetyl radical,

Compounds with radicals which can be split off by hydrolysis are, for example, also those of the formula. '

H-alk-O-Ph-O-CH ^ -CH- -GH ,,

2 j, 2

0 K ^ R ₁ - (XI) / ^L

wherein Ph, R, R, and alk have the meanings given above and X stands for the carbonyl or thiocarbony group,

The hydrolysis is carried out in the usual way, for example in the presence of basic agents such as alkali hydroxides, or preferably in the counterv / kind of acidic agents, such as dilute acids, e.g. sulfuric acid or hydrohalic acids, e.g., hydrochloric acid.

Another method of making the compounds of formula I consists, for example, in that one | binding the formula.

R-alk-0-Ph-O-CH ₂ -0H-Y, (XIl)

in which R, Ph and alk have the meanings given above and Y is a radical of the formula

-CH ₂ fN = R | (a) or -GH = NR ₁ (b) where R 'pin on a carbon divalent radical of the type

009841/1978

of R, (i.e. RjH is equal to R,), reduced.

The compound of the formula XIIa can also be in the form of the ring-tautomeric compound of the formula

R-alk-O-Ph-O-ÖH -CH GH ₀

² II ²

0 NH. (XIII)

are present.

The reduction can be carried out in a customary manner, for example by catalytic hydrogenation, however care must be taken that the unsaturated hydrocarbon residue R is not attacked. Preferably one leads reduction with di-light metal hydrides such as lithium aluminum hydride or sodium borohydride.

The new compounds of the formula I can also be obtained by using a compound of the formula

R-alk-O-Ph-O-CH 1 -CH 0

² II

0 NH \ /

^R i

wherein R, alk and Ph have the meanings given and Ri is a divalent radical of the type R 1 on a carbon atom, reduced.

Complex metal hydrides, such as lithium aluminum hydride or diisobutyl aluminum hydride, are primarily used as reducing agents in terms of

0098U / 1978

The implementation is carried out in the usual way, especially in an inert solvent such as an ether, .-., such as diethyl ether or tetrahydrofuran.

In connection part you can get in the context of the Modify end products in the usual way, introduce substituents or split off or compounds obtained can in are usually converted into other end products.

For example, you can obtain compounds .j of the formula I in their condensation products with aldehydes or Transfer ketones. This is preferably done by repositioning of the compounds of the formula I with an aldehyde or ketone, e.g. one of the formula X = 0, in which X has the meaning given or a reactive carbonyl derivative thereof.

Reactive carbonyl derivatives are above all Acetals, ketals, hemithioketals, thioketals, in particular Dimethyl or diethyl acetals, ketals or thioketals, or acylals, especially those with acetic acid or with *

a hydrohalic acid, for example compounds of the formulas XCl ₂ or XBr ₂ , in which X has the above meaning.

This reaction is carried out in the usual manner, in the presence or absence of a solvent, at room temperature or preferably at elevated temperature, if necessary in the presence of a condensing agent, in particular 'one acidic condensate Sj carried out.

Obtained condensation products of compounds of formula I with aldehydes or ketones, i.e. e.g.

009841/1978

'- 20U346

Bonds of the formula Ia can be added to the compounds in a customary manner of formula I are hydrolyzed. The hydrolysis is preferably carried out in acidic solution, for example as described above.

Depending on the process conditions and starting materials the end products are obtained in free form or in the form of their salts, which is also included in the invention. the Salts of the end products can be converted into the free base in a manner known per se, e.g. with alkalis or ion exchangers will. The latter can be converted into organic or inorganic acids, especially those which are suitable for the formation of therapeutically useful salts win salts. Examples of such acids are called: hydrohalic acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, amber, Glycol, milk, apple, wine, lemon, ascorbic, maleic, Hydroxymaleic or pyruvic acid; Phenylacetic, benzoic, p-aminobenzoic, anthranil, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, emboxylic acid, methanesulfonic, ethanesulfonic, Hydroxyethanesulfonic, ethylonsulfonic acid; Halobenzenesulfone, Toluenesulfonic, naphthalenesulfonic or sulfanic acid; Methionine, tryptophan, lysine or arginine.

Read or other salts dor new compounds, such as /..D. dio Plier ate, can also be used to clean the obtained.

000841/1978

serve free base by converting the free bases into salts, separates these and in turn frees the bases from the salts. As a result of the 'close relationships between the new Compounds in 'free form and in the form of their salts are meaningful in the preceding and below under the free base and expediently, if appropriate, also to understand the corresponding salts.

The invention also relates to those embodiments

shape the process, after which one goes from one to any Stage of the process runs out as an intermediate compound and carries out the missing process steps, or where you get a starting material under the reaction conditions forms, or in which the reaction components are optionally present in the form of racemes, optical antipodes, isomer mixtures and / or salts * For example, you can use a. Connection of

Formula Ij with an amine of the formula RyNHg and; a ketone i or aldehyde der'Formel X -0 react. Depending on the choice of reaction conditions, a compound of the formula III or I is obtained as an intermediate, which then reacts according to the invention * to form the oxazolidine. .

You can also use an amine of the formula

"'■■' ■ OH

R-alk-0-Ph-O-CH ₂ -CH-CH ₂ -NH ₂ , (IV)

009841/1978

OH

" ^l6 " 20H346

in which R., alk and Ph have the meanings given, react with an aldehyde or ketone of the formula Ri = 0, in which R ^{f has} the meaning given, in the presence of suitable reducing agents, with the intermediary of the Schiff base of the formula XII a shown above or the tautomeric oxazolidine of the formula XIII is formed.

But you can also use an aldehyde of the formula

R-alk-O-Ph-0-CH ₂ -CH-CHO, '(XV)

wherein R, alk and Ph have the meanings given, with an amine. of the formula R, -NH, in which R, has the meaning given has to react in the presence of suitable reducing agents, with the Schiff'se shown above as an intermediary Base of the formula XII b is formed.

Depending on the choice of starting materials and working methods, the new compounds can be present as optical antipodes or W racemates, or, provided they contain at least two asymmetric carbon atoms, also as isomer mixtures (racemic mixtures).

Any isomer mixtures (mixtures of racemates) obtained can be separated into the two stereomeric (diastereomeric) pure racemates in a known manner on the basis of the physico-chemical differences between the constituents, for example by chromatography and / or fractional crystallization.

009841/1978

■ - ■ ". - ■■ ■■■ · - 17 -:; ■ '■: - -.- ν: -'--- .. ■ <■" ■ "

Obtained ftacemates can be broken down into the antipodes by known methods, for example by converting crystallization "from an optically active solvent, with the help of microorganisms or by reaction with a, optically active salts forming with the chemical compound Acid and separation of the salts obtained in this way, e.g. due to their different solubilities in the Diastereomers that make up the antipodes by the action of suitable Funds can be released. Particularly common ones optically active acids are e.g. the D- and L-forms of tartaric acid, di-o-toluyltartaric acid, malic acid, Mandelic acid, camphorsulfonic acid or quinic acid. It is advantageous to isolate the more effective of the two antipodes.

For carrying out the reactions according to the invention, it is expedient to use those starting materials which to the groups of end products particularly mentioned at the outset, and especially to those specifically described or highlighted lead raised end products.

The starting materials are known or can, if so they are new, can be obtained by methods known per se.

Compounds which have a radical which can be split off by hydrolysis on the nitrogen atom and / or on the 2- hydroxyl group are obtained, for example, by condensation of a compound of the formula

009841/1978

(XVI)

or a compound of the formula

R-alk-O-Ph-0-CH ₂ -CH CH (XVII)

N / ⁷

with a compound of the formula

Y ₁ -R ₁ (XVIII)

where Ph, R and alk have the meanings given above, and in the condensation of compounds XVI and XVIII X _{p is} hydrogen or a radical which can be split off by hydrolysis and one of the radicals X and Y .. is a reactive esterified hydroxyl group and the other denotes an amino group which is optionally substituted by a removable radical, and in the condensation of compounds XVII and XVIII Y-, denotes an amino group substituted by a removable radical, and where R, has the meanings given above.

Furthermore, these compounds substituted on the nitrogen and / or on the 2-hydroxyl group are also thereby obtainable that one ρ- (R-alk-0) -Phenol, wherein R and alk have the meanings given above, or a salt thereof with a compound of the formula

X'-CH _O CH-CII -NR ₁ or CH ^ r-CH-CH -NR ₁

² I ² I ¹ ^ ^_0/2 I ¹ οχ. X ₂ ^ - x ₂

009841/1978

converts, wherein X 'is a reactive esterified hydroxyl group and at least one of the radicals X and Xp through Hydrolysis is cleavable residue and the other is optionally hydrogen *

A third possibility, the mentioned, substituted on the nitrogen atom and / or on the 2-hydroxyl group Getting connections consists in being in connections the formula

R ^ Ik-O-Ph-O-CH ₀ -CH-CH ₀ -NR ₁ ·,

dd 1

wherein R and alk have the meanings given above and one of the radicals X and X 'is hydrogen and the others represent hydrogen or a radical which can be split off by hydrolysis, the radical or radicals which can be split off in a customary manner Manner, e.g. by acylation. .

Compounds with cleavable by hydrolysis ■ Remnants of the formula

; ■. ·. I OH.

² II ² (χι)

0 N-R.

- ■■ .-. x

in which X is the carbonyl group or thiocarbony group, and Ph, R and alk have the meanings given above, can also be obtained by reacting 1-amino or 1- (NH-Ry) -2-hydroxy-3- [ρ- ( R-alk-0) -phenoxy] -propanes with reactive derivatives of carbonic acid or thiocarbonic acid, such as carbonic acid or thiocarbonic acid diesters, carbonic acid or

00 98 4.1 / 197 8

20U346

Thiocarbonic acid halide esters, carbonic acid or thiocarbonic acid dihalides, Carbon disulfide or especially phosgene or thiophosgene can be obtained, or by ring closure of compounds of the formula

OH

R-alk-O-Ph-O-CH-CH-CH -NR ^r

I ₁

γ »

where Y ^{1 is} a reactive derivative of the carboxyl group, P is a thio or dithiocarboxyl group, and R 'is the radical R or hydrogen. Such derivatives are, for example, esters, such as alkyl or phenyl esters, halides, such as chlorides or bromides, amides, such as diphenylamides, or anhydrides, for example those of the formula -N = C = O, N = C = S, -NR ¹ COOR "or NR'CSOR ", where R 'is the *. Has meaning and R "stands for an acyl radical, especially that of a carboxylic acid. In the N-unsubstituted compounds obtained, the radical R _{1 is introduced} in a known manner, for example by reacting the sodium compound ^ with a reactive ester of the alcohol R, OH.

The invention also relates to the new starting materials which already have the 1- $ JHR,) ~ 3- [p- (R-alk-O) -phenoxy] -propane structure contain, such as those on the nitrogen atom and / or the 2-hydroxy group by hydrolytically cleavable radicals substituted starting materials; these also have an effect on the circulatory system and can accordingly be used as medication be used.

009841/1978

■■. ■ .- · ■■■ - 21 - ■■ - ■ -. -, "■ -. ■■ ■

The new compounds can be used, for example, in the form of pharmaceutical preparations, which they can be used in free Form or in the form of their non-toxic salts mixed with one, e.g. for enteral or parenteral administration suitable pharmaceutical, organic or inorganic, contain solid or liquid carrier material. For education the same substances come into question that with the

. "■■ - * ■ ·. ·· - ■ '' new compounds do not react, such as water, gelatin, lactose, starch, stearyl alcohol, magnesium stearate, "i Talc, vegetable oils, benzyl alcohol, rubber, polyalkylene glycols, Petroleum jelly or other known excipients-. The pharmaceutical preparations can e.g. as tablets, Dragees, pills, capsules or in liquid form as solutions (e.g. as elixir or syrup), suspensions or emulsions. If necessary, they are sterilized and or or contain auxiliaries such as preservatives, stabilizers, Wetting or emulsifying agents, solubilizers, g salts for changing the osmotic pressure or buffers. The dose to be used depends on the type of condition being controlled and the individual patient. at used intravenous or intramuscular administration for example, ampoules of 1-3 mg, especially 2 mg, Active ingredient. The daily dose can range between 1 and 3 mg, for example »Pharmaceutical preparations for Oral administration advantageously contain 10-30 mg, in particular 20 mg of active ingredient per dose and the

Q0 & 8417 197 *

- U2 -

-20U346

daily dose can for example be between 10 and 120 mg.

The pharmaceutical preparations can also contain other therapeutically valuable substances. Thus, in addition to the above-mentioned new compounds, the pharmaceutical preparations can contain other cardiovascular agents and / or psychotropic agents such as tranquillizers. For example, they can include vasodilator, in particular narerweiternde coro- jk compounds such as in particular vasodilating esters of nitrous acid or nitric acid, especially nitroglycerine, pentaerythritol tetranitrate,

λ: triethanolamine trinitrate, nitromannitol, also papaverine, theobromine, theophylline, oxyethyltheophylline, hihydroxypropyltheophylline and other coronary-expanding derivatives of theobromoiris and theophylline, as well as 2-ethyl-3- (3 ^t , 5 ^l -diiodo-4 ¹ -.hydro) , 2,6-bis (diethanolamino) -4,8-d! Piperidino-pyrimido (5,4-d] pyrimidine, N-3 ^f -phenylpropyl- ™ (2 ¹ ) -1,1-diphenylpropyl- (3 ) ~ amine or adenosine The preparations for oral administration are formulated, for example, so that the daily dose results in 5-50 mg of an active compound of the formula I or Ia and 5-50 mg pentaerythritol tetranitrate, the administration expediently taking place three times a day.

The pharmaceutical preparations are obtained using customary methods.

The following examples illustrate the invention without them ioduch a Kuachränküti. The temperatures are in CeIsLusgrnfion stated.

009841/1978

■■■■■ ·. -.23 -. . ^: "■■■■ ■■ '■■■■.." Λ

Example 1 ·

A mixture of 22 g. l- (p-allyloxyphenoxy) -2J, 3-epoxy-propane, 22 g of isopropylamine and 22 ml of ethanol during% hour un-ter stirring to 90 ervmrmt. It is then concentrated in vacuo at .80 °, the residue is dissolved in 2-n. Hydrochloric acid, and. extracted with ether. The aqueous phase is separated off and made alkaline by adding concentrated sodium hydroxide solution. The precipitated base is extracted with methylene chloride. After drying and evaporation of the solvent, the l-isopropylamino-2-hydroxy-3- (palIyloxyphenoxy) propane of the formula remains.

I / 3

CH ₂ -CHGH ₂ -NH-CH

CH-

back, which melts at 77-79 ° after sublimation. The hydrochloride melts at 123-124 °.

The 1- (p »-Allyloxyphenoxy) -2,3-epoxy-propane used as starting material can be prepared as follows:

25 g ρ-allyloxyphenol, 25 g epichrorhydrin and 25 g of potash in 250 ml of acetone are used for 12 hours heated to 70 ° with stirring. The potash is then filtered off and the filtrate evaporated in a vacuum. The return

009841/197

20U346

stand is dissolved in methylene chloride and the solution with 2-η. Sodium hydroxide solution shaken out. After drying and evaporating the organic phase, the crude 1- (p-allyloxy-phenoxy) -2 * 3-epoxy-P ^r remains OPAN back, which is further used directly.

1-Isopropylamino-2-hydroxy-3- (ρ-methallyloxy-phenoxy) -propane can be prepared in an analogous manner produce.

Example 2

A mixture of 35 g of 1- (p-propargyloxy-phenoxy) -2,3-epoxy-propane, 35 g of isopropylamine and 40 ml of ethanol are heated to 80 for 4 hours. Then you steam in a vacuum, dissolves the residue in 2-n. Hydrochloric acid and extracted with ether. Add to the aqueous phase Sodium hydroxide solution until an alkaline reaction, and then the precipitated oil is extracted with methylene chloride. To drying and evaporation of the solvent leaves 1-isopropylamino-2-hydroxy-3 (p-propargyloxy-phenoxy) -propane the formula

/. ν I / 3

CH = O-CH _n -O- ^ VO-OH _n -OH-CH-MH-CH ² χ / 2 2 \

OH,

back, whose O'yelohexylsulfamat melts at 112 -t 113 °. The aluminum raw material wounded epoxy can can be produced as follows:

ÜÜ9041 / 1973

A mixture of 81 g of ρ-propargyloxyphenol, 8θ g Epichlorohydrin, 80 g of potash and 800 ml of acetone is under Stir cooked for 12 hours. Then filtered ■ the potash is removed and evaporated in a vacuum. The residue is dissolved in methylene chloride and extracted with 2-n. Caustic soda. After drying and evaporation of the solvent what remains is the crude l- (p-propargyloxyphenoxy) -2,3-epoxypropane as OeI, back.

Example 3

A mixture of 20 g of 1- (p-allyloxyphenoxy) -2,3-epoxy-propane, 20 g tert. Butylamine and 20 ml of ethanol heated to 80 ° for 4 hours, then evaporated in a vacuum and dissolves the residue in 2-n. Hydrochloric acid. The solution is extracted with ether and then passed through j | Addition of caustic soda made alkaline. It separates an oil, which is extracted with methylene chloride. To the 1-fcert remains after drying and evaporation of the solvent. -Butylamino) -2-hydroxy-3- (p-allyloxyphenaxy) -propane the formula '.--. "

CH ^ CH-CH.

back, whose cyclohexyl sulfamate sohmllsst ^{at I27-X28 0.}

009841/1978

CH ₉ -CII-CH -ISH-Gh-

'■ 20U346

Example 4

20 g of l- (p-allyloxyphenoxy) -2,3-epoxy-propane, 20 g of cyclopropylamine and 20 ml of ethanol are heated to 80 hours for h and then evaporated in vacuo. The residue is dissolved in 2-n. Hydrochloric acid and extracted with ether. The acid phase is prepared by addition of soda lye W alkaline and extracted the separated oil with methylene chloride. After drying and evaporation of the solvent, 1-cyclopropylamino-2-hydroxy-3- (p-allyloxyphenoxy) propane of the formula remains

OH

CH ₂ = CH-CH ₂ -O- < ^ V ) -O-CH ₂ -CH-CH ₂ -NH-I

back, which melts ^{at 68-69 0} after recrystallization from petroleum ether.

Example 5

To a solution of 12.0 g of 1- (p-allyloxyphenoxy) -3-chloro-2-propanol 9> 0 g are slowly added to 50 ml of ethanol Isopropylamine and then heated to 70 ° for 5 hours The reaction mixture is evaporated in vacuo. The residue one solves Ln 2-n. Hydrochloric acid and extracted with ether. The aqueous layer is separated off, alkaline with sodium hydroxide

003841/1978

set and extracted with ether. Do the drying and evaporation of the solvent leaves a gel which slowly crystallizes.- By recrystallization from hexane becomes "1-isopropylamino-2-hydroxy-3- (p-aülyioxy-phenoxy) -propane obtained melting at 77-79 ^. The hydrochloride melts at 123-124 °.

The 1- (p-allyloxyphenoxy) -3-chloro-2-propanol used as the starting material is made by reacting 3- (p-allyloxyphenoxy) -l, 2-epoxypropane with hydrochloric acid obtained * ": The compound boils at 121-135 ^ / 0.1 mm. ':

Example 6

A solution of 14 g of 1-isopropylamino-2-hydroxy-3 ^- (p-allyloxyphenoxy) propane and 7. g of benzaldehyde in 140 ml of benzene is refluxed for 6 hours, the water formed being separated off. The solvent is then removed by distillation in a water-jet vacuum. The residue is distilled at 0.1 mm Hg, the 2-phenyl-3-isopropyl-5- (p-allyloxyphenoxymethyl) oxazolidine of the formula .-. ".- ... -

CH = GH-CH -0- <( ^ VO-OH-CH

098 4 1 / .19.7

20U346

is contained in the fraction boiling at 175-185.

Example 7

20 g ρ-allyloxyphenol, 15 g 3-isopropylamino-2-hydroxy-1-chloropropane and 20 g of finely ground potash are stirred at 50 in 300 ml of acetone for 5 hours. The undissolved portion is filtered off and the acetone solution is evaporated in a water-jet vacuum. The residue will dissolved in ether and with 2-n. Extracted sodium hydroxide solution. The ether layer is separated off and evaporated to dryness. What remains is the l-isopropylamino ^ -hydroxy ^ -Cp-allyloxyphenoxy) propane, which melts at 77-79 after sublimation. The hydrochloride melts at 123-124 °.

Example 8

A solution of 15.0 g of 1-amino-2-hydroxy-3- (ρ-alIyloxy-phenoxy) -propane and 8.0 g of isopropyl bromide in I5O ml of ethanol is added after adding 5jÖ g of potash during Heated to the boil for 4 hours. The undissolved portion is then filtered. The piltrate is evaporated. The residue becomes with 100 ml 2 ~ n. Hydrochloric acid refers and with Author extracted. The wnsHorigö layer siteJ.lt, one with

BATH ORIGINAL 009841/1978

10-η. Caustic soda alkaline and extracted the excreted Base with ether. The after drying and evaporation of the The residue remaining in the solvent is recrystallized several times from hexane. 1-Isopropylamino-2-hydroxy-3- (p-allyloxyphenoxy) propane is obtained in this way in crystals of P. 77-79 °. P. des Hydrochloride 123-124 °.

The l-amino-2-hydroxy-3- (p-allyloxy-phenoxy) -propane used as starting material can be produced in the following way: - %

p-Benzyloxyphenol is reacted with epichlorohydrin in the presence of potash in acetone. The 3- (p-benzyloxyphenoxy) -1,2-epoxy-propane thus obtained is allowed to react with benzylamine and the two benzyl groups are removed in the 1-benzylamino-2-hydroxy-3- (p-benzyloxyphenoxy) propane obtained by catalytic hydrogenation in the presence of palladium carbon. The 1-amino-2-hydroxy ~ J> - (ρ-hydroxyphenoxy) -propane thus obtained is then condensed in the presence of sodium ethy'late in ^ ethanol with allyl bromide. ■ = * -

Example 9

A solution of 15.0 g of 1-amino-2-hydroxy-3- (ρ-allyloxy-phenoxy) -propane in 3Q ml of ethanol and 30 ml of ace clay is refluxed for 5 hours. here one evaporates in a V / aüserstrahlvakuum. Dor residue. is dissolved in If) O ml of methanol and, with stirring

C) 0 8 9 £ 1/1 9 1 3 ^BATH

'. 20U346

to the solution 5.0 x g sodium borohydride. After 4 hours there add 300 ml of water and 100 ml of 2-n to the reaction mixture. Hydrochloric acid. The aqueous solution is extracted with ether and then by adding 10-n. Sodium hydroxide solution made alkaline. It is extracted twice with ether, the extract is dried over sodium sulfate and evaporated in vacuo. Man. receives an oil that slowly crystallizes: by recrystallization petroleum ether becomes l-isopropylamino-2-hydroxy-3- (p-allyloxyphenoxy) propane obtained from the F. 77-79 °. F. of the hydrochloride 123-124 °.

Example 10

\ 10.0 g of 3-IsoP * Opyl-5- (p-allyloxy-phenoxymethyl) -oxazolidinon- (2) are heated with 50 ml of 10 N sodium hydroxide solution for 15 minutes with good stirring to 120th 200 ml of water are then added and the mixture is extracted with ether. The ether layer is separated off, dried and evaporated in a water jet vacuum. What remains is the 1-isopropylamino-2-hydroxy-3 ~ (p-allyloxyphenoxy) propane, which melts at 77-79 ° after recrystallization from hexane. The hydrochloride melts at 123-124 °.

The 3-isopropyl ^f j- (ρ-aLlyloxy -phenoxymuUhyl) -oxasoLidinon- (2) used as starting material can, for example, (lur-'ht / ni ·,!?, Oa from ^f ? Ί ο uLly Lo ^ yphonoxymothyl) -oxazolidinone

(2) · in the presence of sodium hydride with isopropyl bromide in Toluene can be obtained *. ^

..-, ... Example 11

Tablets containing 20 mg of active substance are made in the following composition _:

1-isopropylamino - ^ - hydroxy-J-Cp-allyl- -; oxy-phenoxy) -propane-hydrochlopia _;

Lactose

colloidal silica.

Talc magnesium stearate

mg

20th mg 60 mg 50 mg 5 mg 9 mg 1 mg

Example 12

The following mixture is used to produce capsules:. '

l-Isopropylamino-2-hydroxy-3- (p- * aliyl- ν

oxy-phenoxy) -propane hydrochloride. 2500g

Talc 80 g

colloidal silica 20 g

The active ingredient is made with talc and colloidal silica intimately mixed, the mixture passed through a sieve (0.5 mm)

0 0 9841/197 8 BADORiQSKAL

20H346

and filled in portions of 21 mg in hard gelatine capsules of suitable size.

Example I3

1 g l- (N-acetyl-isopropylamino) -2-acetoxy ~ 3- (pallyloxy -phenoxy) -propane is dissolved in 7 ml of absolute ethanol and 3j5 ml of 3-n. Sodium hydroxide solution at reflux for 7 hours cooked. The reaction solution is concentrated in vacuo. The residue from evaporation is mixed with water and shaken with Aether off. After evaporation of the dried ethereal solution the residue obtained is 1-isopropylamino-2-hydroxy-3- (p-allyloxyphenoxy) propane from F. 77-79

Example 14

lOjO g 1- (N-acetyl-isopropylamino) -2-hydroxy-3- (p-allyloxyphenoxy) propane are dissolved in 100 ml of ethanol. After adding 25 ml of 5-n. Hydrochloric acid is boiled for 3 hours under reflux and then evaporated in vacuo. The residue is dissolved in water and by adding 2-n. Sodium hydroxide solution made alkaline. It crystallizes that 1- (isopropylamino) -2-hydroxy-3- (p-allyloxyphenoxy) propane which, after recrystallization from hexane, melts at 77-79.

00 9 8 A1 / 1978

BAD ORiGiNAL

- .20Ί4346

Example 15.

12.0 g of 1- (isopropylamino) -2- (benzoyloxy) -3- (pallyloxyphenoxy) propane are dissolved in 100 ml of ethanol and after adding 30 ml of 2-n. Sodium hydroxide for 1 hour refluxed. This is then evaporated in a vacuum and the residue crystallized from petroleum ether. 1- (isopropylamino) -2-hydroxy-3- (p-allyloxyphenoxy) propane is obtained in this way from m.p. 77 - 79

009841/1978 '

Claims (1)

'. 20U3A6 Patent claims /l./ Process for the preparation of l- (sec.amino) -2-hydroxy-3- [p- (R-alk-0) -phenoxy] -propanene the formula OH , (D wherein alk is an alkylene radical and R is an unsaturated aliphatic hydrocarbon radical, R _{1 is} an aliphatic hydrocarbon radical with up to 15 carbon atoms, which can also be interrupted by heteroatoms such as oxygen, sulfur or nitrogen and / or can be substituted by hydroxyl groups, a cycloaliphatic Hydrocarbon radical with up to 15 carbon atoms or an optionally substituted araliphatic hydrocarbon radical with up to 15 carbon atoms _Ä , and Ph means an optionally substituted 1,4-Phenylenr'est, and their condensation products with aldehydes or ketones, characterized in that one Compound of formula X " R-EIk-C-Ph-O-CH ₂ -CH-CH ₂ -X ¹ , (II) wherein R, alk and Ph have the meanings given, X "is the hydroxyl group and X ^{1 is} a reactive esterified hydroxyl group or X" and X ¹ together is an epoxy 009841/1978 '' 20H346 form a group, with an amine of the formula R, -NHp, wherein R, has the meaning given, or a condensation product thereof with an aldehyde or .. ketone or in a compound of the formula,, _ _; OH
CH ₂ -CH-CR ₂ -NH ₂ , (IY) wherein R, alk and Ph have the meanings given, or into a condensation product thereof with an aldehyde or; Ketone introduces the radical R or a phenol of the formula R- alk - 0 - Ph - OH, wherein R, alk and Ph have the meanings given, with a compound of the formula where R, has the meaning given, X "is the hydroxyl group and X ^{f is} a reactive esterified hydroxyl group, or X" and X ^! ^ together form an epoxy group, or with a condensation product of a compound in which X "denotes the hydroxyl group, with an aldehyde or ketone or in a compound of the formula OH , "' wherein Ph and R have the meanings given above, or in a condensation product thereof with an aldehyde or 009841/1 9 7 8 ' Ketone substituted the phenolic hydroxyl group in the usual way by the radical R-alk-, in which R and alk are those given above Have meaning - or in a 1- (R, -amino) -2-hydroxypropane, that in the 3-position is the remainder of the formula R - alk - O - Ph - O -, in which R, alk, Ph and R _{1 have} the meanings given, and which has a radical which can be split off by hydrolysis on the nitrogen atom and / or on the 2-hydroxy group, or a compound "of the formula" OH R-EIk-O-Ph-O-CH ₂ -CH-Y, (XH) in which R, Ph and alk have the meanings given above and Y is a radical of the formula -CH ₂ -N = R | (a) or -CH = NR ₁ (b) in which Rj is a radical of the type R 1 which is divalent on a carbon, it also being possible for the compound of the formula XIIa to be present in its tautomeric form, reduced, or a compound of the formula R-alk-O-Ph-O-CH ₂ -CH C 0 NH (XIV) in which R, alk and Ph have the meanings given and Rj is a divalent radical of the type R on one carbon atom, reduced and, if desired, obtained Veri ^: ii: ü :: ' Ii Φ c Γ Γ ¹ :''I ^! 'iiiri'll 1''- ι: -!' 1 ;: οη mil Λ1Φ Μ "! · 'Μ r.-. Ir Γ Ketones or reactive carbony derivatives thereof in converts into the corresponding oxazolidines or oxazolidines obtained to the corresponding compounds of the formula I hydrolyzed and / or optionally obtained isomer mixtures separates and / or obtained Eacemate split into the optical antipodes and / or obtained salts into the free bases or free bases obtained are converted into their salts. 2. The method according to claim 1, characterized in that that you can get a compound of the formula B-alk-O.-Ph-O-CH ₂ -CH-CH ₂ -X ¹ , (il) wherein R, alk and Ph have the meanings given, X " ^{denotes the hydroxyl group and X 1} a reactive esterified hydroxyl group or X" and X ¹ together form an epoxy group, with an amine of the formula R, -NH_, in which R _{1 has} the other jfl has the given meaning, or converts it into a compound of the formula Oh R -alk-0-Ph-0-CH ₂ -CH-CH ₂ -NH ₂ , (IV) in which R, alk and Ph have the meanings given, or in a condensation product thereof with an aldehyde or ketone introduces the radical R ₁ or a phenol of the formula R - alk - 0 - Ph - OH , (Vl) 00 9841/1978 * ' '. 20U346 wherein R, alk and Ph have the meanings given, with a compound of the formula where R, has the meaning given, X "is the hydroxyl group and X ^{1 is} a reactive esterified hydroxyl group or X" and X ¹ together form an epoxy group, or with a condensation product of a compound in which X "is the hydroxyl group, with an aldehyde or Ketone converts or in a 1- (R, -amino) -2-hydroxy-propane, which is in "3-position the remainder of the formula R - alk - 0 - Ph - 0 -, wherein R, alk, Ph and R- have the meanings given, and that on the nitrogen atom and / or on the 2-hydroxy group has a radical which can be split off by hydrolysis, which splits off or a compound of the formula · OH R-alk-O-Ph-0-CH ₂ -CH-Y, (XIl) in which R, Ph and alk have the meanings given above and Y is a radical of the formula ₂ -N = R ^ (a) or -CH = NR ₁ (b) wherein Ri is a divalent radical of the type R, is reduced and, if desired, compounds of the formula I obtained by reaction with aldehydes or Ke- Q09841 / 1978 clays converted or obtained into the corresponding oxazolidines Oxazolidines hydrolyzed to the corresponding compounds of the formula I and / or obtained racemates of the formula I split and / or preserved into the optical antipodes Salts in the free bases or obtained free bases in their salts transferred. 3 .. The method according to claim 2, characterized in that a compound of formula 11, wherein R, alk and Ph have the meanings given, X "is the hydroxyl group and X ^{1 is} a halogen atom or an arylsulfonyloxy group or X" and X ¹ together form an epoxy group, .reacts with an amine of the formula R, NHp, in which R _{1 has} the meaning given. 4. The method according to claim 1, characterized in that a compound of the formula II in which R, alk and Ph have the meanings given, X " ^{denotes the hydroxyl group and X 1} denotes a halogen atom or an arylsulfonyloxy ™ group or X" and X. ¹ together form an epoxy group, .with a compound of the formula R ₁ - N = X, (HI) " in which R _{1 has} the meanings given, and X is an optionally substituted alkylidene group. 5, method according to claim 2, characterized in, that one is a compound of the formula IV or a condensation product of which with an aldehyde or ketone with 0 0 984 J / 1 8 7.8 .. 20U346 a compound of the formula R-.X ¹ in which X ^{1 is} a halogen atom or an arylsulfonyloxy group. 6. The method according to claim 2, characterized in that a compound of the formula VI with a compound of the formula VII in which X "is the hydroxyl group and X ^{1 is} a halogen atom or an arylsulfonyloxy group or X" and X ¹ together form an epoxy group, or with a condensation product of a compound in which X ″ denotes the hydroxyl group with an aldehyde or ketone. 7 · The method according to any one of claims 2 and 6, characterized in that the compound of the formula VI is used in the form of a metal salt or in the presence of a suitable salt formation with the phenol of the formula VI Condensing agent works. 8. The method according to any one of claims 3 and 5 bis 7, characterized in that X ^{1 is} a chlorine or bromine atom. 9. The method according to claim 1, characterized in that that a compound of the formula IX with a compound of the formula R - alk - X ¹ , 0 0 H R U / 1 π '7 8' ^ - 2Q14346 wherein R and alk have the meanings given in claim 1 and X 'is a reactive esterified hydroxyl group means, implements, and, * if desired, connections obtained of the formula I is converted or obtained into the corresponding oxazolidines by reaction with aldehyde or ketones Oxazolidines hydrolyzed to the corresponding compounds of the formula I and / or obtained racemates of the formula I split into the optical antipodes and / or preserved - ^; - '"■' ■ '■ A Salts in the free bases or obtained free bases in their salts transferred. 10. The method according to claim 9, characterized in that the compound of formula IX is used in the form of a metal salt or in the presence of a condensation agent suitable for salt formation with the phenol of formula IX; 11. '"The method according to any one of claims 9 and 10, characterized in that one ^{starts from compounds of the formula R-alk-X 1} , wherein X ^{1 is} a halogen atom or an arylsulfonyloxy group; 12. The method according to any one of claims 9 to H #, characterized in that one ^{starts from compounds of the formula R-alk-X 1} , wherein X ^{1 is} a chlorine or bromine atom . 009841/1970 . 42 - '- 20U3A6 13 · The method according to claim 1, characterized in that a compound of the formula HO-Ph-CKCH-CH CH _n 2 j, 2 j, o If-R ₁ . , (X) in which Ph and R _{1 have} the meanings given and X denotes an optionally substituted alkylidene group, with a compound of the formula R - alk - X ¹ , '* wherein R and alk have the meanings given in claim 1 and X ^{1 is} a reactive esterified hydroxyl group. 14. The method according to claim 13, characterized in that that the compound of the formula X is used in the form of a metal salt or in the presence of one for salt formation with the phenol of the formula X suitable condensing agent is working. 15. The method according to any one of claims 4, 13 and 14, characterized in that X ^{1 is} a chlorine or bromine atom. 16. The method according to claim 2, characterized in that one is a 1- (R, -amino) -2-hydroxy-propane, which is the remainder of the formula in the 3-position R - alk - 0 - Ph - O -, 009841/197 8 " wherein.R, alk, Ph and R, have the meanings given, and that on the nitrogen atom and / or on the 2-hydroxy group has an acyl radical of a carboxylic acid, hydrolyzed . 17. 'The method according to claim l6, characterized in that the aeyl radical is a lower alkanoyl radical. 18. - The method according to claim 2, characterized marked- ((J net that .man a compound of the formula -. '_ R-alk-O-Ph-O-CH -CH -CH ₀ ¹ , 2. . . 0 NR ₁ , (XI) ο, wherein Ph, R, R and alk have the meanings given in claim 1 have and X stands for the carbonyl or thiocarbonyl group, hydrolyzed. . : ■■■: ■■ ^{:. :} ■■ I 19 · The method according to claim 2, characterized in that the compound of formula XII with a Dileichtmetallhydrid reduced. 20. The method according to claim 1, characterized in that that the compound of formula XIV with Jiithiumaluminiumhydrid or ditsobutyl aluminum hydride reduced. 0 0 9 8 4 1 /! 978 21. The method according to any one of claims 1 to 20, characterized in that from one to any Stage of the process runs out as an intermediate compound and carries out the missing process steps, or forms a starting material under the reaction conditions, or the reaction components, if appropriate used in the form of racemates, optical antipodes, isomer mixtures and / or salts. 22. The method according to claim 21, characterized in that a compound of formula II with an amine • of the formula · R, NH and a ketone or aldehyde of the formula X = O converts. 23 · The method according to claim 21, characterized in that that an amine of the formula IV with an aldehyde or ketone of the formula Ri = 0, in which Rj is that given in claim 1 Has meaning, converts in the presence of suitable reducing agents. 24. The method according to any one of claims 2 to 3> 5 to 8, 16 to 19, 22 and 23, characterized in that compounds of the formula pfno '1' * 9 7 9 wherein alk is a lower alkylene radical and R is a lower unsaturated aliphatic hydrocarbon radical and R- means an aliphatic hydrocarbon radical, produces. 25. The method according to any one of claims 2 to 3, 5 to 8, 16 to 19, 22 and 23, characterized in that one compounds of the formula wherein alk is a lower alkylene radical and R is a lower unsaturated aliphatic hydrocarbon radical, an aliphatic hydrocarbon radical and X is a lower alkylidene radical. 26. The method according to any one of claims 2 to 3> 5 to 8, 16 to 19 * 22 and 23, characterized in that one compounds of the formula R-alk wherein alk denotes a lower alkylene radical and R denotes a lower unsaturated aliphatic hydrocarbon radical, and R denotes a secondary or tertiary lower alkyl radical having up to 5 carbon atoms. 00984 1/1978 -A6 - '- 20U346 27 · Method according to one of Claims 2 to 3, 5 to 8, 16 to 19, 22 and 23 * characterized in that one compounds of the formula R-alk wherein alk is a lower alkylene radical and R is a lower one unsaturated aliphatic hydrocarbon radical, R_ denotes a secondary or tertiary lower alkyl radical with up to 5 carbon atoms and X is a lower alkylidene radical. 28. The method according to any one of claims 2 to 3, 5 to 8, 16 to 19, 22 and 23 * characterized in that compounds as defined in any one of claims 24 to 27 are used Kind in which R-alk denotes the allyl, methallyl or Wk propargyl residue means, produces. 29. The method according to any one of claims 2 to 3, 5 to 8, 16 to 19, 22 and 23, characterized in that one compounds of the formula. . OH -NH-R ₃ , wherein R-alk- denotes the allyl, methallyl or propargyl radical means and R ^ for the tert. Butyl radical or the Isopro-3 pylrest stands, manufactures. 009841/1978 , ■ · 20H3A6 3Oi method according to one of claims 2 to 3 * 5 to 8, 16 to 19, 22 and 23, characterized in that the 1-isopropylamino-2-hydroxy-3- (p-allyloxyphenoxy) propane is produced. 31. The method according to any one of claims .2 to 3, 5 to 8, 16 to 19, 22 and 23, characterized in that the l-isopropylamino-2-hydroxy-3- (p- ^{metal: i} allyloxyphenoxy) propane manufactures. , - _ 32. · The method according to any one of claims 2 to 3 * 5 to 8, 16 to 19, 22 and 23, characterized in that the 1-isopropylamino-2-hydroxy-3- (p-propargyloxyphenoxy) propane is produced. 33., The method according to any one of claims 2 to 3 # 5 to 8, 16 to 19, und.22 to 32j, characterized in that the new compounds are in the form of their racemic mixtures
or produces racemates. 34. The method according to any one of claims 2 to 3 * 5 to 8, 16 to 19 and 22 to 32, characterized in that the new compounds are produced in the form of their optical antipodes. 00984.1 / 1-978 20H346 35 · Method according to one of Claims 2 to 3 * 5 to 8, l6 to 19 and 22 to 34, characterized in that that the new compounds are produced in the form of their salts. 36. The method according to any one of claims 2 to 3 * 5 to 8, 16 to 19 and 22 to y \, characterized in that the new compounds are produced in free form. 37 · method according to one of claims 9 to 12, characterized in that one compounds of the formula OH -CH-CH -NH-R wherein alk is a lower alkylene radical and R is a lower one means unsaturated aliphatic hydrocarbon radical and R, means an aliphatic hydrocarbon radical, manufactures. 38. The method according to any one of claims 9 to 12, characterized in that compounds of the formula OH R-alk-0- <f y -O-CH-CH-CH -NH-R wherein alk is a lower alkylene radical and R is a lower unsaturated one aliphatic hydrocarbon radical means, and R represents a secondary or tertiary lower alkyl radical with up to 5 carbon atoms. 0098 / <1/1978 ' 39 · The method according to any one of claims 9 to 12, characterized characterized in that compounds of the type defined in one of claims 37 or 38, in which R-alk denotes the allyl, Methallyl or propargyl radical means, produces. 4Q "The method according to any one of claims 9 to 12, characterized in that compounds of the formula f j R-alk-0- < ^ ^ -Q-CH-GH-CH-NH-R <f wherein R-alk- denotes the allyl, ■ 'Methallyl or propargyl radical and R., for the tert. Butyl radical or the isopropyl radical stands, manufactures. 41, method according to one of claims 9 to * 12, characterized characterized in that the l-isopropylamino-2-hydro xy-3- (p-methallyloxyphenoxy) propane. 42. The method according to any one of claims 9 to 12, characterized characterized in that 1-isopropylamino-2-hydroxy -3- (p-allyloxyphenoxy) propane produces. 43. The method according to any one of claims 9 to 12, characterized characterized in that 1-isopropylamino-2-hydroxy -3- (p-propargyloxyphenoxy) -propane produces. 009841/1978 ". 20U346 44. The method according to any one of claims 9 to 12 and 37 to 43, characterized in that the new Compounds in the form of their racemic mixtures or racerates manufactures. 45. The method according to any one of claims 9 to 12 and 57 to 43, characterized in that one has the new Establishes connections in the form of their optical antipodes. · 46. The method according to any one of claims 9 to 12 and 37 to 45, characterized in that one has the new Manufactures compounds in the form of their salts. 47. The method according to any one of claims 9 to 12 and 37 to 45, characterized in that the new compounds are produced in free form. 48. * Method according to one of claims 1, 4, I3 to 15, 20 and 21, characterized in that compounds of the formula OH R-alk-0 ^ V wherein alk is a lower alkylene group and R represents a lower unsaturated aliphatic hydrocarbon radical and R, is an aliphatic Kohlenwaseerstoffrest, manufactures. 009841/197 8 -.51 - '■ ■ .... · ■ 49 · Method according to one of Claims 1, 4, 13 to 15, 20 and 21, characterized in that compounds of the formula ·. R-all where alk is a lower alkylene radical and R is a lower ~ v unsaturated aliphatic hydrocarbon radical means;: R- is an aliphatic hydrocarbon radical and X is one means lower alkylidene radical, produces. 50. ^{4 The} method according to any one of claims 1, 4, 13 to 15, 20 and 21, characterized in that compounds of the formula . OH-j R-alk-0— <ζ y —O-CH -CH-CH -KH-R_, wherein alk is a lower alkylene radical and R is a lower one denotes unsaturated aliphatic hydrocarbon radical and R denotes a secondary or tertiary lower alkyl radical with means up to 5 carbon atoms, produces. 51 · Method according to one of Claims 1, 4, 13 to 15, 20 and 21, characterized in that one compounds the formula 00 9 84 1/197 8 ' 20U346 R-alk- ( Ν : S * j NO, wherein alk is a lower alkylene radical and R is a lower unsaturated aliphatic hydrocarbon radical, R., a secondary or tertiary lower alkyl radical with up to 5 carbon atoms and X a lower alkylidene radical means, manufactures. 52. The method according to any one of claims 1, 4, I3 to 15, 20 and 21, characterized in that one of the compounds defined in one of claims 48 to 51 Type in which R-alk denotes the allyl, methallyl or propargyl radical, produces. 53. The method according to any one of claims 1, 4, I3 to 15, 20 and 21, characterized in that compounds the formula OH A \ R-alk- ( wherein R-alk- denotes the allyl, methallyl or propargyl radical means and R ^ for the tert. Butyl radical or isopropyl rest stands, manufactures. 0 0 9 8 k 1/1 9 7 8 54. The method according to any one of claims 1, 4, 13 to 15, 20 and 21, characterized in that the 1-isopropylamino-2-hydroxy-3- (p-allyloxyphenoxy) propane manufactures. 55 * Process according to one of claims 1, 4, 13 to 15, 20 and 21, characterized in that - that the l-isopropylamino-2-hydroxy-3- (p-methallyloxyphenoxy) propane ^ is prepared, * * ' ~ * 56. The method according to any one of claims 1, 4, 13 to 15, 20 and 21, characterized in that the " 1-isopropylamino-2-hydroxy-3- (ρ-propargyloxyphenoxy) propane manufactures. 57 · The method according to any one of claims 1, 4, I3 to 15, 20, 21 and 48 to 56, characterized in that -k the new compounds are prepared in the form of their racemic mixtures or racemates, 58. The method according to any one of claims 1, 4, 13 to 15, 20, 21 and 48 to 56, characterized in that the new compounds in the form of their optical antipodes manufactures ;. 59 · Method according to one of Claims 1, 4, 13 bia 15, 20, 21 and 48 to 58, characterized in that 009841 / 19-7 8- * ' '. 20H346 the new compounds are produced in the form of their salts. 60. The method according to any one of claims 1, 4, I3 to 15j 20, 21 and 48 to 58, characterized in that the new connections are made in free form. 009841/1978 * 6l. The according to the method of one of the claims 1 to 60 connections received * 62 »Compounds of the formula * OH
R ^ Ik-O-Ph-O-CH ₂ -CH-CH ₂ -NH-R ₁ , (i) wherein alk is an alkylene radical and R is an unsaturated aliphatic hydrocarbon radical, R is an 'all- ' μ phatic hydrocarbon radical with up to 15 carbon atoms, which can also be interrupted by heteroatoms, such as oxygen, sulfur or nitrogen, and / or substituted by hydroxyl groups can, represents a cycloaliphatic hydrocarbon radical with up to 15 carbon atoms or an optionally substituted araliphatic hydrocarbon radical with up to 15 carbon atoms, and Ph represents an optionally substituted 1, U-phenylene radical, and their condensation products with M aldehydes or ketones. 63 · Compounds of the formula OH R-alk-0- < ^ y-Q-GH-CH-CH -MH-R, wherein alk is a lower alkylene group and R represents a lower unsaturated aliphatic hydrocarbon radical and R, is an aliphatic hydrocarbon radical. 00984 % / 19 7 8 * -. 64. Compounds of Formula R-alk-O - </. ^N > —O-CH -CH CH " 2 ι ι 2 0 N — R, wherein alk is a lower alkylene radical and R is a lower one unsaturated aliphatic hydrocarbon radical, R denotes an aliphatic hydrocarbon radical and X denotes a means lower alkylidene radical. 65 · Compounds of the formula OH ι R-alk-0- < f ^) - O-CH -CH-CH -NH-R, wherein alk. a lower alkylene radical and R a lower unsaturated aliphatic hydrocarbon radical and R is a lower alkyl radical with up to 5 carbon atoms. 66. Compounds of Formula OH ι R-alk-0- < f ^ > -0-CH-CH-CH-NH-R wherein alk is a lower alkylene radical and R is a lower unsaturated aliphatic hydrocarbon radical and R 1 is a secondary or tertiary lower alkyl radical with up to 5 carbon atoms. Π 0 Π Γ> ζ i / 1 P. 7 R 20U346 67 · Compounds of the formula R-al where älk is a lower alkylene radical and R is a lower unsaturated aliphatic hydrocarbon radical, --R- __ ■■ - ■ "_ ■■ ■.. ■ ■ ■ -ν j -" ■ a secondary or tertiary lower alkyl radical with Ms to § 5 carbon atoms and X _{a means} a lower alkylidene radical 68.. Compounds according to one of Claims 63 to 67 * where R-alk- denotes the allyl, methallyl or propargyl radical means· 69. Compounds of Formula OH R-alk-O— <? . ^ y- 0-CH ₂ -CH-CH ₂ -NH-R ₃ , wherein R-alk- denotes the allyl, methallyl or propargyl radical and R., for the t.ert. Butyl or isopropyl radical. ' 70. 1-Isopropylamino-2-hydroxy-3- (p-allyloxyphenoxy) propane. 009-1 / 1978 '■ - 20U3A6 71 · 1-Isopropylamino-2-hydroxy-3- (ρ -methallyloxyphenoxy) propane. 72. 1-Isopropylamino-2-hydroxy-3- (ρ-propargyloxyphenoxy) propane. 73 · 1- (tert-butylamino) -2-hydroxy-3- (p-allyloxyphenoxy) propane. 7 ¹ ^ · 1-Cyc lopr opy lamino -2 -hydroxy -3- (ρ -ally loxyphenoxy) -propane. 75 ·. 2-phenyl-3-isopropyl-5- (p ~ allyloxyphenoxymethyl) oxazolidine. 76. One of the compounds mentioned in one of claims 62 to 75 in the form of their racemate mixtures or racemates. 77 · One of the compounds mentioned in one of Claims 62 to 75 in the form of their optical antipodes. 78. One of the compounds mentioned in one of claims 62 or 77 in free form. 009841/1978 ■■ - 59 - ^: ■. '■ 201A346 79. One of those mentioned in one of claims 62 to 77 Compounds in the form of their salts. 80. One of those mentioned in one of claims 62 to 77 Compounds in the form of their therapeutically useful salts. -. "■" ■ ' 81. Pharmaceutical preparations containing one of the in one of the .Ansprüche 62 to 78 and 80 mentioned compounds together with a therapeutically usable carrier material. 82. Process for the preparation of compounds of the formula. . * R-alk-O-Ph-O-CH -CH 0H ₀ ² II ² . ο 0 NR _n Μ ¹ ■ '■ " wherein alk is an alkylene radical and R is an unsaturated aliphatic Hydrocarbon radical means, R, an aliphatic Hydrocarbon residue with up to 15 carbon atoms, which can also be interrupted by heteroatoms such as oxygen, sulfur or nitrogen and / or by Hydroxy groups can be substituted, a cycloaliphatic hydrocarbon radical with up to 15 carbon atoms or an optionally substituted araliphatic 0 0 9 8 41/19 7 8 _ä <.;: ·, · 201A346 Hydrocarbon radical with up to 15 carbon atoms .Ph represents an optionally substituted 1,4-phenylene radical and X for the carbonyl or thiocarbonyl group is, characterized in that a 1- (R, -NH) -2-hydroxy-3- [p- (R-alk-0) -phenoxy] -propane with a reactive di-derivative of carbonic acid or thiocarbonic acid or a compound of the formula OH I ■ 'R-alk-0-Ph-O-CH-CH-CH -N-R, γι where Y 'stands for a reactively modified carboxyl, thiocarboxyl or dithiocarboxyl group, intramolecularly condensed or a compound of the formula R-alk-O-Ph-O-CH -CH CH ₀ 2 ι ι 2 O NH preferably in the form of its sodium salt, with a reactive ester of an alcohol of the formula R ₁ OH or a compound of the formula R-alk-O-Ph-OH
or a salt thereof with a compound of the formula 0098A1 / 1C7 8 * 2GU346 X'-CH-CH- T-GK _n ² II ² NO. wherein-X- ^{1 is} a reactive esterified hydroxyl group. means, converts and, if desired, optionally obtained Isoraerengemische separates and / or obtained Racemate splits into the optical antipodes. ■■ '"·'" ■ ■■ ■■■ ·. ■■ ■■ "ι 8y. Compounds of the formula ·! R-alk-O-Ph-O-CK.-CH- II ² 0 Eh-R _n ■ ο .. ■■ _ ■ ■■. wherein alk is an alkylene radical and R is an unsaturated aliphatic hydrocarbon radical, R is an aliphatic hydrocarbon radical with up to 15 carbon atoms, which can also be interrupted by heteroatoms, such as oxygen, sulfur or nitrogen, and / or can be substituted by hydroxyl groups, a cycloaliphatic hydrocarbon radical with up to 15 carbon atoms or an optionally substituted araliphatic hydrocarbon radical with up to 15 carbon atoms, Ph represents an optionally substituted 1,4-phenylene radical and X _{Q represents} the carbonyl or thiocarbonyl group. 0 0 9 8 A 1/19 7 8 '- 20H3A6 Compounds of the formula R-alk-O-Ph-C-CH-CH CH ₀ 2 j ι 2 wherein X stands for the carbonyl or thiocarbonyl group, alk denotes a lower alkylene radical and R denotes a lower unsaturated aliphatic hydrocarbon solid and R. a secondary or tertiary lower alkyl radical. means with up to 5 carbon atoms. . 85.. ^ -Isopropyl-S-Cp-allyloxy-phenoxymethyl) -oxazolidinone- (2). 86. · Pharmaceutical preparations containing one of the compounds mentioned in one of claims 85 to 85 together with a therapeutically usable carrier material. 00 98 A1 / 1978